Advice on CFSAN'S Draft Report:

Approaches to Establish Thresholds for Major Food Allergens and for Gluten in Food








Friday, July 15, 2005


8:00A.M. to 9:45 A.M.





Greenbelt Marriott

6400 Ivy Lane

Grand Ballroom


Greenbelt, Maryland 20770


                         P A R T I C I P A N T S




       Richard A. Durst, Ph.D. - Acting Chairman

       Jeffrey A. Barach, Ph.D. (Industry Representative)

       Patrick S. Callery, Ph.D.

       Dennis Gonsalves, Ph.D., M.S.

       Jean M. Halloran (Consumer Representative)

       Douglas C. Heimburger, M.D., M.S.

       Margaret C. McBride, M.D.

       Mark Nelson, Ph.D. (Industry Representative)

       Carol I. Waslien Ghazaii, Ph.D., R.D.




       Petr Bocek, M.D., Ph.D.

       Margaret Briley, Ph.D., R.D.

       Erica Brittain, Ph.D.

       Ciaran P. Kelly, M.D.

       Soheila June Maleki, Ph.D.

       David O. Oryang

       Marc D. Silverstein, M.D.

       Suzanne Teuber, M.D.




       Robert E. Brackett, Ph.D. - Director

       Food and Drug Administration, CFSAN


       Catherine Copp, J.D. - Senior Policy Advisor

       Food and Drug Administration, CFSAN


       Steven M. Gendel, Ph.D. - Senior Scientist

       Food and Drug Administration

       National Center for Food Safety and Technology


       Rhonda Kane, M.S., R.D. - Consumer Officer

       Food and Drug Administration, CFSAN


                   P A R T I C I P A N T S (Continued)




       Michael M. Landa, J.D.

       Deputy Director for Regulatory Affairs

       Food and Drug Administration, CFSAN


       Stefano Luccioli, M.D. - Senior Medical Advisor

       Food and Drug Administration, CFSAN


      Marcia Moore, Food Advisory Committee, Executive Secretary


                             C O N T E N T S



Call to Order and Welcome and Introductions                5

 Richard Durst, Ph.D., Acting Chairman                   


Welcome                                                                                  6

Robert E. Brackett, Ph.D., Director, CFSAN, FDA            


Committee's Discussion and Response to                             7

FDA's Charge and Questions                                  


Closing Comments                                                                    85       

Michael M. Landa, J.D., Deputy Director

Regulatory Affairs, CFSAN, FDA                            


Adjournment                                                                              87                                          


                          P R O C E E D I N G S


Call to Order and Welcome and Introductions


                 CHAIRMAN DURST:  I would like to convene


       the final session of our committee meeting this


       morning.  Let me begin by again stating that there


       are the conflict of interest statements over on the


       side table for anyone who wants to avail themselves


       of that information.


                 Also, rather than waiting for the very


       last minute to thank the various people who made


       this meeting possible, I just wanted to thank


       Marcia and her staff for taking such good care of


       us and providing all of the information we needed


       to have a successful meeting.


                 I also want to thank the USDA Graduate


       School for providing support and the Marriott Hotel


       of course for providing very nice facilities to do


       this work.


                 In addition, I would also like to take the


       opportunity to introduce Dr. Robert Brackett, who


       is the director of the Center for Food Safety &


       Applied Nutrition, who was able to join us for a


       couple of hours this morning.


                 Bob, if you want to say a few words?




                 DR. BRACKETT:  Thanks, Dick.


                 The only thing I wanted to say -- I know


       you are all in a hurry to get things done and get


       to your airplanes this morning, too -- I had hoped


       to be here for more of the meeting this week, but I


       have been stuck at other meetings.  However, I do


       want to let you know how supportive I am of the


       advisory committee structure.


                 I served on this Committee a number of


       years ago, and I know that it is a big time


       commitment and there is a lot of studying to be


       done, a lot of discussion, so FDA really does


       appreciate your participation and your expertise.


                 This is something I think that has more


       value added to it for us than we could have gotten


       individually and breadth of knowledge, and so I do


       thank you also.


                 I would also like to extend that I hope


       that you will continue.  I hope that you will tell


       your colleagues, when they are asked to serve on


       this Committee, that this is something that they


       really do provide a great service to the country


       and to the regulated industry that we deal with.


                 With that I will let you conclude your


       meeting this morning, and thank you for being here.


                 CHAIRMAN DURST:  Thank you, Bob.




                 DR. TEUBER:  I found out, in my rush to


       get over here, one page is still on the printer at


       the concierge desk.  If there is a Marriott staff


       person who could pick up the third page from the


       printer, behind the concierge desk, that would be


       fantastic.  It is a printout of just a draft of our


       summary here.


                  Committee's Discussion and Response to


                        FDA's Charge and Questions


                 CHAIRMAN DURST:  Okay.  Thanks, Suzanne.


                 I assume I don't have to read the charge


       again, since we know what we are here for.  We have


       been dealing with this for two days now.


                 To remind you, we don't have to come up

       with, certainly, a vote.  We don't even have to


       come up with a consensus.  What we want to do is


       provide the FDA with some guidance and


       recommendations on the draft report that we have


       been discussing the past two days.


                 I have asked several members of the


       Committee to try to summarize the remarks or


       comments and discussion that has gone on for the


       past two days.


                 I have asked Marc and Suzanne to summarize


       the food allergens part of our first day of


       discussions and Ciaran to summarize the celiac


       disease, the gluten portion.


                 After their presentations, we will open it


       for discussion to make any comments agreeing,


       disagreeing or just filling in some blanks that


       they think are important.


                 Then, after that part, we will go back and


       deal with the general questions that are on the


       charge sheet.  That I think should go fairly


       quickly after we have agreed on some of the other


       items that we are going to discuss.


                 Even though it is out of order, maybe we


       will start with Dr. Kelly with the discussion of


       gluten, since we are waiting for the page on the


       food allergens.




                 DR. KELLY:  Sure.  Ciaran Kelly here.


       Should I read the questions, or just go straight to


       the answers?


                 DR. TEUBER:  Yes, please.


                 DR. KELLY:  So the first question is


       regarding gluten and celiac disease.  Is there a


       distinct subpopulation of individuals with celiac


       disease that have an increased sensitivity to




                 If so, for the safety-assessment-based


       approach, is the proposed uncertainty factor for


       intraspecies differences tenfold sufficient to


       ensure that exposure levels will be below the level


       of sensitivity for this highly sensitive


       subpopulation?  If this uncertainty factor tenfold


       is not sufficient, what uncertainty factor should


       be used?


                 Sensitivity to gluten does vary from one


       individual to another at the level of clinical


       symptoms.  However, symptoms of celiac disease do


       not parallel small intestinal mucosal injury as


       assessed by small bowel biopsy histology, which is


       the widely accepted quantitative method of


       assessing gluten-induced injury in celiac disease.


                 There are insufficient available data to


       state with any certainty or to what extent


       individual variations influence the intestinal


       mucosal changes of celiac disease in response to


       specific levels of gluten exposure.  Thus, it is


       not possible currently to assign a reliable


       uncertainty factor for intraspecies differences in


       gluten sensitivity.


                 The Committee is uncertain as to whether


       or not it is appropriate to apply an uncertainty


       factor for intraspecies variation in the


       immunological responses to gluten and celiac


       disease that is based on the standards normally


       used for toxicology studies.


                 The magnitude of the uncertainty factor


       will also be influenced by the level of individual


       variation observed in the studies used to determine


       that threshold.  The choice of an uncertainty


       factor for a dietary gluten threshold will also be


       influenced by the ability to measure the gluten


       content of foods.


                 It is likely that the gluten threshold


       together with a modest or moderate uncertainty


       factor will lie close to the lower limits of


       performance of the currently available assays and


       this may, at least in the short-term, dictate the


       measurable threshold.


                 CHAIRMAN DURST:  Okay.  Does anyone have


       any comments or discussion on Ciaran's presentation


       on that question?


                 (No response.)


                 CHAIRMAN DURST:  I guess most people are


       in agreement on that.  Very good.


                 DR. KELLY:  The second question:  Is it


       scientifically sound to use data from short-term


       clinical studies that evaluate the effects of acute


       gluten exposure to predict the effects of long-term


       gluten exposure in gluten-sensitive individuals?


                 What uncertainty factor is appropriate for


       thresholds developed using available short-term


       clinical studies in order to prevent adverse


       effects associated with chronic effects.


                 Data from acute challenge studies that


       examine intestinal mucosal changes in response to


       brief exposure to gluten peptides of several hours


       or days' duration are not widely accepted as a


       valid method to determine a gluten threshold.


                 However, there is general acceptance in


       the medical and scientific community of studies


       that examine mucosal responses to several weeks or


       months of exposure.


                 If threshold values are based on challenge


       studies that examine in a quantitative fashion the


       mucosal responses to several weeks or months of


       gluten exposure, then the uncertainty factor needed


       for chronic exposure will be minimal.


                 Additional valuable data are also


       available from other countries, particularly in


       Europe, that have many years of experience with


       enacted threshold values.  Those data may also


       reduce concerns regarding the need for an increased


       uncertainty factor based on prolonged duration of


       gluten exposure.


                 Since a determination of threshold values


       must be made in the context of incomplete and


       evolving medical and scientific knowledge, the


       Committee endorses the Working Group's finding that


       any threshold value that may be set for gluten must


       be continually reevaluated, and, if new information


       warrants, be adjusted.


                 CHAIRMAN DURST:  Erica.


                 DR. BRITTAIN:  Okay.  I guess I just want


       to summarize.  I have a slightly different


       perspective on this.  I don't think my bottom line


       is really that different.  But from a statistical


       perspective, it is hard for me to know that a


       three-month exposure study would tell me everything


       about the cumulative, chronic exposure; so, I would


       be a little more uncertain than some of the people


       on the Committee were yesterday.


                 However, that concern is softened by the


       fact that we do have the observational data that


       seem to suggest a similar effect; so, I think my


       bottom line is probably pretty similar to yours,


       although maybe a little more uncertainty.


                 CHAIRMAN DURST:  Thank you.


                 Anyone else?




                 MR. ORYANG:  Yes.  David Oryang.  I think


       your concern is well-taken.  I think the key thing


       here is to remember that if it is clearly


       documented or at least if evidence documents how we


       came about determining that safety factor, that is


       the key thing.


                 As long as it is documented and


       transparent, then people will be able to comment on


       it or provide better information to determine


       better safety factors.


                 The clear thing is that there should be a


       good documentation of how the safety factor came


       about.  I think that is the key so that experts and


       others who review it can then give better comments


       or suggestions on how to improve it, if it doesn't


       seem right.


                 CHAIRMAN DURST:  Okay.  Thank you.


       Any other comments?


       (No response.)


                 CHAIRMAN DURST:  I guess we can proceed.




                 DR. KELLY:  The third question:  Are


       current data sufficient to conclude that a portion


       of celiac patients are or are not also susceptible


       to gluten proteins naturally occurring in oats,


       i.e., prolamines and glutelins, if not, what


       additional data is needed to draw such a




                 Published data indicate that the majority


       of individuals with celiac disease do not


       demonstrate significant symptoms or signs in


       response to oats.


                 A meta-analysis of these published studies


       may serve to strengthen this conclusion.  There are


       a very small number of documented cases where


       individuals with celiac disease showed an


       immune-based response to oat proteins.


                 However, the low frequency of these


       reports indicate that the overall approach to


       setting a threshold for gluten should not be unduly


       influenced by the relatively minor concern


       regarding oat-sensitivity.  Of greater concern is


       the issue of cross-contact leading to low-level


       contamination of foodstuffs with the known toxic


       gluten proteins.


                 CHAIRMAN DURST:  Thank you.




         (No response.)


                 CHAIRMAN DURST:  Good.  Thank you.


                 DR. MALEKI:  Well, I have one.


                 CHAIRMAN DURST:  Oh, I'm sorry.


                 DR. MALEKI:  Soheila Maleki.  Just one


       comment.  The other concern that I think wasn't


       mentioned is that limiting the food choices of the


       people that are celiacs is probably self-included.


       I just wanted to mention that.


                 CHAIRMAN DURST:  Okay.


                 DR. KELLY:  Then, the fourth question:


       Are all individuals with celiac disease equally at


       risk for developing consequences -- for example,


       cancer -- and increased mortality from the


       long-term ingestion of gluten?


                 Are current data from clinical studies or


       from individuals with celiac disease on a


       gluten-restricted diet sufficient to estimate the


       magnitude of any increased risk of mortality for


       these individuals?


                 The outcomes of celiac disease vary


       widely, from lifelong silent disease to fatal


       malignancy.  However, at this time the only


       identified risk factor for bad outcomes, including


       death from malignancy, is poor or absent compliance


       with a gluten-free diet.


                 Prolonged, strict adherence to a


       gluten-free diet clearly reduces the risk for


       gastrointestinal symptoms and nutritional


       deficiency states such as anemia and osteoporosis


       and celiac disease.


                 The available data, though limited and


       imperfect, indicate that prolonged, strict


       adherence to a gluten-free diet also reduces the


       risk for malignancy.


                 Thus, instituting measures that facilitate


       compliance with a strictly gluten-free diet are the


       only known approach to reduce the overall risks


       associated with celiac disease.


       Comments?  Questions?


       (No response.)


                 CHAIRMAN DURST:  Good job, keep going.




                 DR. KELLY:  Question five:  Is


       evidence of minimal intestinal pathological change,


       for example, increased intraepithelial lymphocytes


       following a gluten challenge, an appropriate


       symptom upon which to base a LOAEL for long-term




                 Are other biomarkers such as clinical


       symptoms or more severe intestinal pathological


       changes more accurate predictors of long-term




                 Yes, the characteristic intestinal


       pathological changes of celiac disease, for


       example, reduced villus-to-crypt ratio and


       increased intraepithelial lymphocyte counts


       constitute the widely accepted gold standard for


       celiac disease diagnosis.


                 These changes are also widely accepted as


       the gold standard method for evaluating disease


       activity following a gluten challenge.  Other


       disease markers such as symptoms, antigliadin


       antibody, tissue transglutaminase or endomysial


       antibody levels, or measures of mucosal


       permeability are considered of secondary value in


       quantifying disease activity.


                 CHAIRMAN DURST:  Comments?


        (No response.)


                 CHAIRMAN DURST:  Very good, Ciaran.  Thank


       you very much.


                 I don't know, as far as what is allowed,


       may I ask the Threshold Working Group if they have


       any additional questions or clarifications they


       need on those points?


        (No response.)


                 CHAIRMAN DURST:  Well, we are moving,




                 Okay.  Suzanne and Marc, are you ready to


       present to your comments?


                 DR. TEUBER:  Okay.  Suzanne Teuber here.


       For this discussion, it turned out as we went


       through the questions that there were actually some


       that we did not specifically address in the


       Committee discussion, and so there will be


       discussion that is needed this morning in order to


       answer the charge


                 For the first question: are there distinct


       subpopulations of highly sensitive individuals


       within the allergic population for each of the


       major food allergens?


                 We know that there are huge differences in


       threshold doses and a continuum of reaction


       severity upon ingestion from mild to


       life-threatening for each of the major food




                 However, it is not possible at this time


       to identify "distinct" subpopulations of


       individuals by clinical criteria, previous


       frequency or severity of allergic reactions, or


       threshold responses on a double-blind,


       placebo-controlled, food challenge within


       populations sensitive to specific allergens for


       which thresholds or uncertainty factors can be


       identified.  That is number one.


        Any thoughts on that one?


        (No response.)


                 DR. TEUBER:  Okay.  Then, number two, I


       will hand over to Marc here.


                 CHAIRMAN DURST:  Erica.


                 DR. BRITTAIN:  Yes, I just want to add one


       comment.  In terms of all of these questions about


       the food allergies, from my statistical


       perspective, again, to me the first step here of


       when the Working Group actually is setting a


       threshold is to define what the precise goal of the


       threshold is; in terms of the sensitive population


       or the overall allergic population, what risk level


       is acceptable.  I think that is the first step.


                 DR. SILVERSTEIN:  Actually, these are


       additional comments under one, so why don't I


       continue with that.



                 DR. TEUBER:  Okay.


                 DR. SILVERSTEIN:  The next part of the


       question of number one says:  "If so, for the


       safety-assessment-based approach, how to propose


       uncertainty factors for intraspecies differences


       10-fold, under severity of responses for this


       sensitive population tenfold, sufficient to ensure


       exposure levels will be below the level of


       sensitivity for the highly sensitive populations?"


                 The uncertainty factor for sensitive


       populations is unknown when considering food


       allergy and immune response as compared to classic


       safety assessment and toxicology.


                 The selection of an uncertainty factor for


       allergens should be informed by the distribution of


       the NOAELs and the LOAELs using measures of the


       spread of data such as standard deviation,


       interquartile range or ranges.


                 If reproducible, subjective responses in


       patients with a history of life-threatening


       anaphylaxis are included in setting LOAELs and


       NOAELs, the uncertainty factor might be lower than




                 The selection of thresholds for allergens


       should be informed by evidence of the thresholds of


       NOAELs and LOAELs.  However, as we mentioned, bias


       due to exclusion of the most sensitive individuals


       who have experienced life-threatening allergic


       reactions, anaphylaxis, require caution in using


       currently available data.


                 All currently available published and


       unpublished data should be specifically assessed


       for potential selection, referral bias, and other


       factors that influence the individuals who are


       actually studied.


                 There is also uncertainty due to variation


       between individuals in a population and uncertainty


       due to variation within individuals over time.


       There are inadequate prospective studies performed


       with the goal of seeing if the objective response


       thresholds have changed in patients with persistent


       food allergy, except in those who are expected to


       have developed a tolerance.


                 A highly sensitive individual might have a


       lower or higher LOAEL compared to baseline


       depending on such factors as: the season of year;


       theoretically, increased histamine release


       potential based on activity of conditions such as


       allergic rhinitis and asthma, which might be


       seasonal; status of an atopic dermatitis; the time


       of day; stability of the patient's underlying


       asthma; ingestion of other factors such as alcohol,


       exercise, pre- or post-ingestion, matrix effects of


       food, processing the food, progression of the


       degree of their allergy based on IgE target,


       epitope diversification, antibody increases, and


       other variables which are known to individuals in


       the field.


                 The next part of the question:  If these


       uncertainty factors are not sufficient, what


       uncertainty factors should be used for the


       safety-assessment-based approach?


                 A concrete number was not offered by the


       Committee.  The Committee noted that the


       uncertainty levels of tenfold or a hundredfold had


       been used in biomedical toxicology.  IgE-mediated


       allergic reactions essentially are amplifiers.


       They amplify reactions to minute amounts of




                 So, the application of uncertainty factors


       to thresholds on the double-blind,


       placebo-controlled, food challenge may not be


       sufficiently large to handle this variation of


       amplification of an allergic response.


                 DR. TEUBER:  That was the entirety of


       number one.


                 CHAIRMAN DURST:  I beg your pardon?


                 DR. TEUBER:  It was the entirety of number


       one; it is put out in sections.


                 CHAIRMAN DURST:  It is open for






                 DR. BRITTAIN:  I agree with all that.  I


       just want to add one point that as an alternative


       to the uncertainty factors another strategy is the


       modeling approach that we heard the speaker talk


       about.  I think that is a really promising approach


       to assessing risk.


                 However, even with that, you would need to


       make sure that you have data that represents the


       entire target population.  I don't know that really


       is available at this point.


                 CHAIRMAN DURST:  Any other discussion?




                 DR. NELSON:  Yes, this is Mark Nelson.  I


       agree with your synopsis as well, and I think you


       have captured a lot of hours of struggle, but one


       thing I wanted to clarify.  I do agree that the


       uncertainty factors should be based on the range,


       the largest range possible, of the sensitive


       individuals.  But I heard, and correct me if I'm


       wrong, that some of the studies did in fact include


       some extremely sensitive individuals.


                 DR. TEUBER:  Yes, some did.  And then we


       also had the situation where in some studies the


       extremely sensitive people challenges were stopped


       at subjective which -- well, that was in some of


       the hazelnut study.


                 But for the Hourihane study, for instance,


       they did go on.  It was a twenty-fold difference in


       one patient, a fifty-fold difference in the other


       between a subjective response and an objective




                 DR. NELSON:  Right.


                 DR. TEUBER:  We definitely want things to


       be based on objective, when possible, but I am


       concerned that in the threshold studies that are


       going to be done by the consensus protocol there is


       still room for a physician or a patient to decide


       to stop.


                 I mean, they have the ability and informed


       consent procedures to stop at any time, and so if


       they are recruiting the most sensitive, we may have


       folks who back out before an objective response or


       where the physician decides, "Ah, you know, they're


       complaining of throat swelling, and I can't see


       anything, but I'm hesitant to go on."


                 There, that data of the subjective I think


       should be used.  It doesn't carry the weight of an


       objective NOAEL but certainly could be used to help


       estimate an uncertainty factor.


                 DR. NELSON:  Yes.  I don't mean at all to


       imply that people should be forced to participate


       in these studies or continue on, if subjectively


       they have lost comfort.  What I wanted to point out


       was that I understood that the database as it


       exists now, there are some studies that do have


       very sensitive individuals in them.


                 DR. SILVERSTEIN:  I think this is one of


       the most difficult -- this is a discussion point


       not a summary point -- issues is assessing


       potential bias.  There are of course in


       randomized-controlled trials a careful focus on


       eligibility an exclusion criteria.


                 In observational studies and in studies of


       diagnostic test assessment, the eligibility and


       exclusion criteria may or may not be as explicitly




                 In any case, when a study does have


       well-stated eligibility and exclusion criteria, you


       often don't get a description of those people who


       are referred or screened and not studied.  Because


       they are not studied, you usually have less




                 Because this is a serious life-threatening


       condition, because these studies were done at


       distinguished academic centers by individuals who


       have distinct experience, to appear in such a study


       often you need to be referred; and so the referral


       bias, we are often not able to assess it.


                 The strongest studies are those that we


       would call "population-based studies."  Those would


       be the things you would want to look for.


       Oftentimes, that is not stated or it is only


       implicit in understanding that this study, as study


       subjects, the study subjects are often referred to


       as "the population," because we are making


       inferences about similar subjects.  But the study


       subjects, because of referral, weren't truly


       representative of the population of allergic




                 That is the concern, and that is the


       challenge the FDA will have in evaluating this


       literature, but it needs to be looked at for all


       available literature.


                 CHAIRMAN DURST:  Dick Durst.  I would also


       like to remind the Working Group that when they set


       these thresholds they also have to be cognizant of


       the analytical methods.


                 When you put on an uncertainty factor or a


       safety factor onto these thresholds, you have to be


       tempered by the knowledge of what analytical


       methods can do as far as verifying and making sure


       that foods comply to these thresholds.  At the


       present state of the art I think there are some


       problems in this respect, so that this has to be


       taken into consideration.


                 DR. TEUBER:  Suzanne Teuber.  When you go


       through the back of the binder and look at the


       different foods and the sensitivity and actually


       for the objective, quantitative measurements of


       what can be done, if an uncertainty factor is


       applied that is too large, you will be below those


       levels.  You end up then with the analytical method


       as the method of choice for some of these.


                 Additionally, if you consider, the Working


       Group should consider, that the serving size may be


       subject to discussion when you are determining how


       many parts per million may be acceptable.


                 I guess I really need to retract that.  It


       is just that based on clinical experience now so


       many patients go by that first subjective response


       in the mouth of having some tingling or some


       itching and have been able to stop -- I'm sure if


       Anne Munoz-Furlong were here she has thousands of


       stories of this; I have hundreds and hundreds.


                 So, the serving size where a person may


       notice a subjective response may be much smaller


       than the 100-gram serving size that may be used to


       calculate how many parts per million are going to


       be acceptable before a NOAEL with an appropriate


       uncertainty factor applied is reached.


                 CHAIRMAN DURST:  David.


                 MR. ORYANG:  Yes, David Oryang.  Just


       adding, I think, yes, if a safety factor is derived


       in a science-based way, even if the sensitivity is


       much greater than the sensitivity of any of the


       test methods.


                 I think it should be transparently


       communicated, and then the decision will be made,


       hopefully, at FDA as to how to resolve that, maybe


       through labeling and saying, well, it is clear that


       we don't have the methods to be able to detect that


       level, those parts per million that individuals are


       sensitive to.


                 I think the products could be labeled


       appropriately so that those at risk can make the


       choice whether or not to go ahead and take on that


       risk, but I don't think we can temper the science


       based on available methods, necessarily.


                 They are two different things: there are


       the safety issues and then how do we apply what we


       know.  If there is no method of applying or


       detecting that level of sensitivity, then it needs


       to be transparently presented, I think, as opposed


       to altering the safety factor so that it is within


       a range of detectability.


                 CHAIRMAN DURST:  Erica has a comment.


                 DR. BRITTAIN:  Yes.  This is touching on


       something that I tried to say yesterday, and I


       think I said it badly.  Let me take one more chance


       to try to say it again.  At some point the FDA will


       be establishing a threshold for each allergen.  I


       hope it will be a really safe and really


       conservative threshold.


                 Presumably, it will be above the level of


       detection.  It means there will be this gray zone.


       Some products will fall in the gray zones between


       the level of detection and the threshold that was




                 I am wondering if there would be any value


       in being able to provide that information to the


       consumer that this product say something like


       "contains peanuts but below the allergenic level."


                 So, that mom who was here on Wednesday who


       said, "I don't want this threshold based on a


       statistical estimate, I want it based on fact," if


       she does not want to take any chance at all, she


       can see, "Oh, it's in that gray zone, and I don't


       want to take any chance."


                 Or, if someone has had experience in the


       past with reactions in that gray zone, then they


       may think they are the rare individual that cannot


       tolerate that level.  I just wanted to throw that

       out one more time.


                 CHAIRMAN DURST:  Okay.  Carol and then




                 DR. WASLIEN:  Well, one of the problems I


       see with the detection method is that we don't even


       know what the allergen is in a good number of


       cases, so having a good detection method may be


       detecting the wrong thing.  It is that kind of


       problem with detection methods, too, that lead to


       the uncertainty factor.


                 DR. TEUBER:  Suzanne Teuber.  I actually


       disagree with that.  Because if you have a method


       that is just aiming to detect the food, the


       proteins in the food that are allergens are going


       to track along with that measurement.  Just as the


       measurements for gluten, the glutelin fraction


       will track along with the gliadin fraction is




                 If all of our tests so far that are


       measuring the food given are based on total


       protein, it all seems to track together in a


       proportionate way.  I think that is okay.


                 DR. WASLIEN:  You don't see a case where


       protein would be separated and only one of the


       protein fractions would be included in the food and


       therefore safe?


                 DR. TEUBER:  Well, yes, where you have


       casein used or alpha-lactoglobulin or whey as


       separate fractions.


                 DR. WASLIEN:  Yes.


                 DR. TEUBER:  There you do have a situation


       where the challenges that are done to determine the


       NOAELs and LOAELs have been with the whole protein.


       Actually, yes, I do see that as a potential


       problem, but the actual challenge dose that would


       elicit -- actually, yes, that is a good point, to


       think about the separation there.


                 DR. WASLIEN:  Yes, particularly with milk




                 DR. TEUBER:  Yes.


                 CHAIRMAN DURST:  Okay.  Soheila and then




                 DR. MALEKI:  Soheila Maleki.  One comment


       for Erica.  Well, currently the gray area exists


       that is in "may contain" labeling.  You are asking


       for something that already exists that the consumer


       is asking to take away.  They want a more


       definitive response.


                 Second, there are analytical methods that


       can actually go down to measuring one molecule that


       is completely insignificant.  Like I said, on this


       tablecloth here somebody can detect peanut or


       wheat, if they wanted to.  You can go down to a


       molecular level, and washing won't get rid of it,


       that these people will not react to it.


                 There is a limit where allergic people


       will not react, and we do have the detection


       methods.  What happens is we don't have the


       threshold data on the individuals.


                 Still, the consumer is asking for us to


       make some kind of decision on the best data


       available.  I think that is something important to


       think about for the consumer, because that is why


       they are frustrated.


                 CHAIRMAN DURST:  Petr.


                 DR. BOCEK:  Petr Bocek.  Soheila pretty


       much said what I wanted to say because that would


       apply to every product to assess their methods.


       One would be saying, okay, this product doesn't


       have, let's say, peanut at the allergenic


       threshold, yet it contains.


                 Here you go, you are restricting the


       consumer from basically anything.  If you take the


       PCR, you are going to detect peanut everywhere.  So


       I think it is absolutely impossible to apply that


       method.  It has to be the allergenic threshold


       only.  That is what the consumer wants, and that is


       going to make it clear.  I absolutely agree with


       that.  I don't think it is practical.


                 CHAIRMAN DURST:  All right.




                 DR. NELSON:  Mark Nelson.  Just to add to


       that from the practical standpoint of actually


       manufacturers labeling their products, we want to


       communicate clearly to the consumer.  We don't want


       to add anymore gray to it, to the situation at all.


                 If a threshold can be established where


       the great majority of allergic individuals for a

       particular allergen can be benefited by having


       that information, great, but we don't want to add


       to the gray.


                 CHAIRMAN DURST:  Thank you.


                 Any further discussion on this question?


                 (No response.)


                 CHAIRMAN DURST:  That was good.  The next




                 DR. TEUBER:  Number two:  “Is the initial


       objective response seen in a clinical challenge


       study always an adverse effect that poses risk to


       human health?,” is the first part of the question.


                 We said there was discussion of no, it is


       just uncomfortable, but then we kind of wrapped it


       up.  We were making comments at the end, so here is


       what we ended up writing.


                 "Yes, if there is an objective response to


       a food in a double-blind, placebo-controlled study


       performed in a patient with IgE-mediated food


       allergy, this is an adverse effect that poses risk,


       albeit usually low.


                 "The findings from an objective response


       in a double-blind, placebo-controlled, food


       challenge is sufficient for physicians to make


       recommendations that patients avoid specific foods


       and change lifestyle to avoid risk of


       life-threatening allergic responses.  This is


       sufficient to conclude that objective responses are


       associated with allergic reactions that pose risk


       to human health."


                 Any comment on that part of the questions?


                 DR. MALEKI:  Just one quick comment.


                 CHAIRMAN DURST:  Soheila.


                 DR. MALEKI:  Soheila Maleki, sorry.  One


       quick comment that, yes, the subject of milk came


       up and I think when Petr and I were making


       comments on that we were thinking instead of just


       "to human health," we were thinking


       "life-threatening."  That is why we said no.  I


       agree, I believe that we can forward your response.


                 DR. TEUBER:  Okay.  Is it scientifically


       sound to use this response to determine a LOAEL in


       the absence of a NOAEL?  We said no, reactions to


       the first dose, because that was implied in the


       question, mean that the LOAEL could be just a trace


       lower or conceivably a thousand-fold lower.  Such


       data are not useful in the decision-making process.


                 Then, the next part of the question:  For


       the safety-assessment-based approach, is the


       proposed uncertainty factor of tenfold sufficient


       and appropriate to use in the absence of a NOAEL?


       We said no, such data should not be used at all.


                 Then, more on that question:  If a


       clinical challenge study reports a subjective


       response of a lower dose than the dose that caused


       an objective response, should that observation be


       taken into account when determining the appropriate


       uncertainty factor?


                 Again, we have extremely limited data on


       subjective responses and the relationship to


       objective at this point.  We said yes, if using a


       subjective response as the LOAEL, the uncertainty


       factor would be lower.


                 If using the objective response but


       subjective responses were also recorded, the


       uncertainty factor -- and this is a point that we


       can discuss more today -- should probably extend to


       cover the dose at which the subjective response


       occurred and likely a bit further to account for


       the individual variation.


                 I might like to stop right there, because


       we did not actually specifically discuss that.  As


       we were coming up with this, we wrote that.  Again,


       our whole point is that we want the LOAELs to be


       based on objective data.


                 However, if you have subjective data as


       well, which the consensus protocol for threshold


       studies they are now going to be recording this


       subjective data, this might be very useful in


       judging what these uncertainty factors should be.


       I had put here that the factor should actually


       extend a bit below that.  That was without any


       discussion yesterday.


                 How do you all feel about that?  Again,


       this is just our recommendation.


                 CHAIRMAN DURST:  Carol.


                 DR. WASLIEN:  Hi, Carol Waslien.  Since we


       don't know the individual factors that would


       influence the subjective or objective reactions, I


       assume that we have to include that.


                 I would hope that we would accumulate data


       that says this is the kind of range within an


       individual that you might see, because that makes


       it exceedingly low in a sense or the lower limit.


       Over time, I would think that kind of data should


       be accumulated in trials.


                 CHAIRMAN DURST:  Petr.


                 DR. BOCEK:  Well, we didn't discuss it


       originally, but I absolutely agree with that.  In


       practice, imagine you give a patient in a


       double-blind challenge study 100 micrograms of


       peanut, and they say, "I'm itching all over.  My


       mouth is tingling.  I don't feel well."


                 You go on and they develop hives only at


       100 milligrams.  There is absolutely no way I will


       say that 10 milligram is the norm, because they had


       subjective symptoms which to me are significant at


       100 micrograms.  I certainly agree with that




                 CHAIRMAN DURST:  Marc.


                 DR. SILVERSTEIN:  I would like to make a


       comment and an observation.  In our understanding


       the drugs, we have had tremendous benefits by


       improved methodology that have been developed by


       investigators, epidemiologists, and statisticians


       in response to regulatory requirements that were


       developed and industry was focused on because of a


       need to develop drugs to be marketed.


                 It seems to me that in the setting of


       thresholds for allergens there is an opportunity


       here to specify a set of potential biases, a set of


       potential confounding factors that the leading


       investigators in the allergic diseases would use in


       establishing these consensus protocols for


       double-blind, placebo-controlled, food challenges.


                 If, for example, biases such as referral


       bias, selection bias, disease-spectrum bias,


       verification bias were judged to be important




                 A set of standards for performing these


       studies could include reporting this information.


       Journal editors have also been influential in


       improving the quality of studies by saying, "As a


       characteristic for publication, we would like you


       to meet these criteria."


                 If there were a set of confounding factors


       -- time of day, season, exercise, concurrent


       medications -- that are thought to be important by


       clinicians, by allergists, if those factors were


       specified as factors that should be reported in the


       collection of data, then as we go to making


       judgments about policy and regulations, we would


       have a more uniform and higher quality data to base


       those regulations.


                 If we think back about the way in which


       our knowledge of clinical trials has benefited by


       the need to have well-designed Phase I, Phase II,


       Phase III clinical trials, I think we are at an


       analogous point here.


                 These factors that we have, these


       potential sources of error and the potential


       incomplete data, I think could be used by those on


       the cutting-edge in doing these studies or


       designing these studies, so that as these studies


       are conducted within one, two, three years we would


       have a body of data to make better judgments about


       the setting of thresholds.  I think there is a very


       important opportunity here to influence the type of


       data that will be available in a couple of years.


                 CHAIRMAN DURST:  Suzanne.


                 DR. TEUBER:  A note to file, this would be


       an excellent RFA.  Again, these studies are


       extremely expensive, and so the only ones that are


       underway right now or being planned are those being


       sponsored by industry, graciously, to help


       determine these thresholds.  This is an excellent


       opportunity for us, as a Committee, to have in our


       minutes the need for more funding for this.


                 CHAIRMAN DURST:  Jean.


                 MS. HALLORAN:  It does seem like,


       following up on this, one of the critical questions


       is the relationship of subjective responses to


       objective responses.  I don't know whether it has


       been studied so far how well these correlate or


       whether that is something that needs further study.


                 However, if in placebo-controlled,


       double-blind studies a subjective response is a


       very good indicator of a subsequent objective


       response, then that would lend more validity to


       using the subjective responses as a factor in


       determining a threshold.


                 I was wondering if anybody knows whether


       that kind of correlation has been done up to this


       point; and if not, whether perhaps we might want to


       recommend research in this area?


                 DR. TEUBER:  Suzanne Teuber.  That


       actually is being incorporated into the current


       consensus protocol for threshold studies, that


       subjective responses will be recorded carefully,


       and then the goal is to proceed to an objective.


       This will allow us to have data on how those are


       related in a wider range of patients.


                 Because right now, there are only a few


       reports of proceeding on to an objective response


       after initially having a subjective one, I should


       also note, a subjective response verified by repeat


       challenge with negative placebo.  It will come.


                 CHAIRMAN DURST:  Any further discussion on


       question two?


                 DR. TEUBER:  Well, actually we have more


       on question two.  That was just one little


       subsection there.




                 DR. TEUBER:  Suzanne Teuber, I should say.


                 CHAIRMAN DURST:  I thought we went through




                 DR. TEUBER:  Oh, actually, no, you're


       right.  That was basically it, but we have one


       little bit more that we wanted to add to this


       discussion of number two.  We wanted to note again


       this recruitment problem.


                 Of note, recruitment of the highly


       sensitive subpopulations to threshold studies may


       be enhanced by recording subjective reactions that


       are reproducible to the active dose but negative to


       the placebo, two challenges of each, with an option


       of stopping at that dose.


                 In threshold studies, highly sensitive


       patients may or may not be willing to proceed to an


       objective response or the physician may not be



       comfortable proceeding.


                 There is acknowledged controversy that is


       appropriate about the applicability of LOAELs that


       are subjective.  Objective responses are preferred,


       with the concern that it be demonstrated in studies


       that extremely sensitive subjects have been willing


       to participate in, otherwise an uncertainty factor


       greater than 10 may be needed because we just don't


       have enough data.


                 Again, we wanted to note the previous


       comments that Mark had made about using a range of


       threshold values in determining the uncertainty


       factor.  We actually raised these points in our


       discussion here again.


                 Then, proceeding on to number three:  In


       the absence of specific data that would allow


       thresholds to be established for each of the major


       food allergens, is it scientifically sound to use


       the threshold established for a single food


       allergen -- for example, peanuts -- as the


       threshold for all major food allergens?


                 We really did not discuss this much


       further.  I think it could use a little bit more


       discussion.  I said no, it appears from the


       available data that soy thresholds may be higher.


       Such labeling would then restrict diets


       unnecessarily as well as pose hardships to




                 We really didn't discuss the fact that for


       other allergens we don't have much data or adequate


       data, and it might be reasonable to use the most


       stringent one until other data are available.


                 Any thoughts on this?


                 CHAIRMAN DURST:  Erica.


                 DR. BRITTAIN:  I mean, that sounds good,


       just as long as you really are totally competent


       about what is the most stringent factors.


                 CHAIRMAN DURST:  Carol.


                 DR. WASLIEN:  Well, I think there are a


       good number of tree nuts, for example, that we have


       limited data on.  Hazelnuts, yes; but other tree


       nuts, we don't have the data on.  Other allergens,


       the other 200 that aren't part of the 7, we have to


       use something in their place.


                 Perhaps, until those ranges become more


       clearly established, we are safer at using a peanut


       allergen that is the most likely to show a response


       for those foods until they are proven otherwise,


       sort of guilty until proven innocent almost.


                 CHAIRMAN DURST:  Marc.


                 DR. SILVERSTEIN:  Marc Silverstein.  It


       seems to me that a parent making a decision about


       food exposure for a child, a physician making a


       decision to recommend diet for a patient and an


       agency making a policy recommendation for consumers


       and industry, all are faced with difficult




                 The decision threshold and the potential


       decision you might make might be weighed not only


       by the likelihood of making a correct or incorrect


       decision, but the consequences of making a correct


       or incorrect decision.


                 Obviously, a parent making a decision for


       a child, a physician making a decision for a


       patient, and an agency making a decision for a


       population and industry all have different

       thresholds in terms of the value of a


       false-positive or a true-positive recommendation to


       avoid or not avoid, or to change diet or not change


       diet, or to label or not label a specific level.


                 I do think that we are, in some sense,


       changing our perspective.  We are putting on our


       hats or our roles as parents and individuals.  We


       are putting on our judgments as clinicians or


       health care providers, and we are putting on our


       roles as policymakers.


                 I actually think we should be cautious in


       making judgments about how sensitive or specific


       our thresholds would be for a decision about our


       children, our decisions about our parents, and our


       decisions about our public population.


                 I am not sure that I would want -- in


       fact, let me phrase it positively -- I would not be


       comfortable making a decision to be very


       conservative or very liberal, if you will, high or


       low, highly sensitive, or specific when I shift my


       domain from that what I would do for my child to


       that what I might do for my patient or that what I


       might do for an agency's decision.


                 I do have some sense that I would rather


       than say we should be conservative and extrapolate


       from what we know about this other class of antigen


       I might say that right now we have insufficient


       data and cannot make a recommendation.


                 CHAIRMAN DURST:  Dick Durst.  Would it be


       safe to say that for those allergens for which we


       have sufficient data we would set a realistic


       threshold based on that; and for those that the


       data is currently insufficient, that we would use


       the threshold of the most sensitive?


                 DR. SILVERSTEIN:  That would be safe to do


       that, but I feel that I could make some judgments


       with regard to individual patients.  I would be


       cautious about making such a recommendation on a


       policy basis for that.  The consumer might and the


       industry might want guidance.  We may have


       insufficient data to be able to provide that




                 CHAIRMAN DURST:  Soheila and then Jean.


                 DR. MALEKI:  Soheila Maleki.  Well, I

       mean, I agree with you, Marc.  I understand your


       thought, but, again, going back to what the


       consumer wants, the consumer wants us to err on the


       side of caution.


                 I mean, of course that is something that


       you don't want, to lump everybody in.  I a hundred


       percent agree with you.  However, when you hear


       from the consumers, they would prefer that you err


       on the side of caution even in the absence of data,


       which is what it essentially is asking.


                 In the absence of data to pick the most


       sensitive food and set a threshold, I think is more


       comfortable to the consumer or probably would make


       them feel better than to say nothing on the label


       at all.


                 DR. HEIMBURGER:  Or, to leave it


       ambiguous.  Doug Heimburger.  Or, to leave it


       ambiguous, to say "It may contain" or whatever.


                 CHAIRMAN DURST:  Jean.


                 MS. HALLORAN:  Yes.  I think we should


       keep in mind that we are talking about a threshold


       for labeling only.  This is not a threshold for


       excluding the product or taking it off the market


       or anything like that.  Particularly, the problem


       comes with what is the threshold for requiring


       somebody to say, a company to say that "This


       product contains soy"?


                 I think to err slightly, perhaps, in the


       direction of a lower threshold is the appropriate


       course here until it can be shown that certain very


       low levels of soy do not pose any hazard to a


       person with allergies.


                 Because for most people it is not


       relevant; it will not be of interest at all.  What


       we are trying to do here is to try to provide


       information to consumers with a very special




                 CHAIRMAN DURST:  Mark.


                 DR. NELSON:  Yes, Mark Nelson.  Earlier,


       we were talking about gray areas.  I think if we


       went to establishing a threshold based on the most


       sensitive or the most problematic allergen we would


       be completely in the black area.


                 Echoing some of Jean's comments, I think


       if we are to establish a threshold based on the


       most problematic allergen, I can't imagine there


       would be too many companies that would go through


       the process of reformulating a product for soy to


       meet that lower, tight threshold knowing full well


       that there are data that exist that we are getting


       close to better information for a higher threshold


       for soy, and then going back and reformulating


       again to meet that.  In effect, we would be


       postponing providing useful information to a good


       portion of the allergic population, if we were to


       take that tack.


                 CHAIRMAN DURST:  Jeff.


                 DR. BARACH:  Jeff Barach.  I would


       certainly agree with Mark's comments.  One thing I


       would say, though, is that we really from my


       observation have fairly good data on at least four


       of the major eight, and that is comforting to me.


       I wish we had more, but that seems to be what was


       presented to us.


                 If we think about what could happen to


       those other four and we use, say, the lowest level


       for the allergen of highest activity, that bothers


       me a little bit because of what Mark said.


                 I think what we should recognize, though,


       is that we do have sort of a default position.


       Unfortunately, we have a zero tolerance now for


       those allergens, so those products would be




                 It is not like they wouldn't be labeled;


       it is just that they don't have a threshold.  If


       there is any there, any detectable, then it would


       have to be labeled.  There is a default.  We don't


       have to in my mind assign a threshold for


       everything at this point and still protect the




                 CHAIRMAN DURST:  Further discussion?




                 DR. KELLY:  So is the default threshold an


       analytical de facto?


                 DR. BARACH:  I would say it is more


       ingredient-based than analytical.


                 CHAIRMAN DURST:  Petr.


                 DR. BOCEK:  Petr Bocek.  When you say


       "ingredient-based," so that goes back to "may


       contain," or what does it mean?


                 DR. BARACH:  It goes back to the system


       that we are currently using.


                 DR. BOCEK:  Okay.  That is the system we


       are trying to change.


                 DR. WASLIEN:  Don't you mean that you have


       to list all of the ingredients of a food, so it is


       not the "may contain"?  Is it the list of


       ingredients?  Isn't that what you are referring to?


       It doesn't mean he is saying we will stick with the


       "may contain" labeling option.  It is if soybean


       lecithin is added to a food, it is on the list of




                 DR. BARACH:  That's right.  The "may


       contain" part covers the possibility of


       adventitious presence or a contamination during the


       manufacturing as well.  We have the list of


       ingredients, and then we have the "may contain" for


       small amounts that may enter the product.


                 CHAIRMAN DURST:  That was Carol and Jeff




                 Now, Mark.


                 DR. NELSON:  It also covers not only


       additives and potential cross-contact, but it also


       includes the processing aids which are


       intentionally used but really serve no function in


       the finished product, but there may be trace


       amounts of it in the product.  At this point the


       law requires us to do it, to label those as well.


                 DR. TEUBER:  Suzanne Teuber.  Actually,


       for those processing aids, many of them will fall


       under the petitioner notification process.


                 DR. NELSON:  They could.


                 CHAIRMAN DURST:  Any further discussion?


                 (No response.)


                 CHAIRMAN DURST:  No?  We will move on.


                 DR. TEUBER:  Suzanne Teuber going on here.


       The next part of that question was actually: if so,


       which food or foods could serve this function; if


       not, is there a more appropriate method to be used?


       I think people discussed that here.


                 The question is, though, do we have a


       consensus on that for Dr. Durst to write up a


       statement?  I'm not sure that we do.  Do you feel


       that we do?  Because basically this might or might


       not be an appropriate way to proceed.  There were


       concerns raised for and against.  I don't think we


       had really consensus.


                 CHAIRMAN DURST:  Yes.  Well, as I say, I


       don't think we have to reach a consensus as long as


       we can provide some guidance to the FDA as far as


       directions for them to go.


                 I could ask Steve at this point if he


       wants any further clarification on that point.


                 DR. GENDEL:  No, you are correct, it is


       not necessary to reach a consensus but simply


       stating the range of opinions and the basis for


       those opinions.


                 DR. TEUBER:  All right.


                 CHAIRMAN DURST:  Okay.  Thank you.


                 DR. TEUBER:  Suzanne Teuber.  Continuing,


       number four, the draft report discusses the


       available data on the levels of protein present in


       highly refined oils, that is, oil that is


       hot-solvent extracted, refined, bleached and




                 Is there any physiologic reason -- for


       example, food matrix effect denaturation of protein


       -- why the protein levels in highly refined oils


       could not be used as the basis for establishing a


       threshold for other allergenic foods?  Are there


       any other limitations that should be considered in


       applying this approach to the eight allergenic




                 With this there was complete consensus


       that the levels in oils did not apply.  The reasons


       that were raised included the fact that we have


       extremely poor measurement of proteins in oils.  It


       is very unclear as to their validity.


                 Secondly, the points raised about


       denaturation, changing of epitopes and whether the


       proteins in oils actually reflect what folks really


       act to.


                 Then, third, the matrix effect was felt to


       be extremely important and has been backed up by


       studies showing that fat can affect the threshold


       for response.


                 In addition -- let's see was there yet


       another, this is where the printer didn't work on


       that -- we had the configuration changes, we had


       the measurement problems, and then the matrix.  I


       believe those were the three that we had covered.


       That one we were in complete consensus agreement




                 CHAIRMAN DURST:  Has anyone changed his or


       her mind on that?


                 (No response.)


                 CHAIRMAN DURST:  Well, I guess we are


       still in consensus.  Okay, that takes care of those


       specific questions.  Again, I will refer back to


       Steve, if he has anything that he would like


       further discussed on the food allergen part?


                 DR. GENDEL:  I don't believe so.


                 CHAIRMAN DURST:  Okay.  Then, we can move


       on to the general questions on the first page of


       our charge.  I think some of these should be able


       to go fairly quickly, since we have laid all of the


       groundwork now for it.  The first one I will read


       the questions, and then we can discuss.


                 "In addition to the four approaches


       identified by FDA for establishing thresholds


       (i.e., analytical methods-based, safety


       assessment-based, risk assessment-based and


       statutorily-derived) are there other approaches


       that FDA should consider?  If so, please describe


       and explain why FDA should consider them."


                 As I recall, there really weren't many


       other options.




                 DR. BRITTAIN:  I just have a really brief


       comment.  It is not really another method, but just


       that to me the safety assessment-based and the


       risk-assessment based are sort of part of a




                 I don't see them as, necessarily,


       completely distinct in that I would like to see


       more statistical principles brought into the


       safety-assessment-based approach.


                 CHAIRMAN DURST:  Okay.  Soheila.


                 DR. MALEKI:  Soheila Maleki.  I think I


       just brought up one method about celiac disease


       measurements, and that is, possibility for looking


       at T-cell activation, which is more likely to catch


       that amplification of response than analytical


       methods might.  It was just a suggestion, if


       anybody else has any ideas.


                 CHAIRMAN DURST:  David.


                 MR. ORYANG:  Yes.  I would just like to


       echo that.  Yes, the risk-assessment based and the


       safety-assessment-based methods are really distinct


       and separate.


                 However, I think more statistic[s] could


       be brought into the safety assessment-based such as


       using distributions within the safety factor or the


       uncertainty factor, or, for that matter,


       incorporating uncertainty into the threshold by


       using a distribution, and then using Monte Carlo


       simulation to come up with a result, which is a


       distribution, and then maybe looking at the 95th


       percentile or whatever values come up from that


       modeling to set what the ultimate threshold should




                 It is really just adding some aspects of


       risk-assessment into, some methods of risk


       assessment into those factors within the


       safety-assessment methodology, because there are


       two dimensions of uncertainty.


                 If you look at the studies that were done,


       from what I could see there is, first of all,


       uncertainty about how closely or how well we


       capture symptoms or signs.  They observe signs.


       When do the observed signs occur?  Should we use


       the subjective or objective?  Because there is a


       range there as to when the sensitivity is




                 Then, the second part of it is you take


       this study population, does that study population


       truly represent the overall population?  Can you


       then take what you have observed here in this study


       group and project it to the population?


                 We can't say a hundred percent of the


       study population represents the other population,


       so there is uncertainty there.  There are really


       two dimensions of uncertainty as well as, of


       course, the model that we are using.


                 There is uncertainty based on the method.


       There are multiple dimensions of uncertainty.


       Unless we incorporate some statistic[s] into this,


       I don't think we are doing a good job.  I really


       suggesting adding some statistic[s] to some of the




                 CHAIRMAN DURST:  Good.




                 DR. WASLIEN:  Carol Waslien.  I also think


       I'm not sure if population-based studies of groups


       exist that are living on gluten-free diets and are


       included in the risk and safety kinds of categories


       and studies, because they are not clinical trials.


                 I think there is some value to be added to


       looking at population-based evaluations to increase


       your ability to include highly sensitive, to


       increase your ability to ask or collect more data


       on range of responses.


                 Population-based studies such as that,


       although they are crude and messy, would give you a


       better idea of the kinds of ranges of responses


       that you would see in the free-living population as


       opposed to a sample, challenge trial kind of


       clinical study.


                 CHAIRMAN DURST:  Well, Marc and then




                 DR. SILVERSTEIN:  I don't have a


       suggestion for another approach.  However, within


       the approach, I was struck by the choice of a 10


       percent proportion, a population that would respond


       to a milk allergy in an identification of a


       hypoallergenic formula to derive a buff sample size


       of about 29 subjects using a conventional


       95-percent confidence interval to identify a


       proportion or a rate of 10 percent as a basis for


       what has become an accepted sample size for these


       sorts of studies.


                 Indeed, it is difficult to do the studies.


       They are expensive; they are risky; and it takes


       time to recruit subjects.  These conditions perhaps


       are not very common; so, referral in the collection


       of an adequate number of patients means that, by


       and large, investigators are performing studies of


       about that size.


                 We have a collection of literature which


       is maybe sufficient for one purpose but may not be


       sufficient to make estimates of thresholds.


       Estimates of thresholds are not estimates of a


       certainty about an incidence rate of 10 percent,


       but it is a measurement of a quantity around which


       we can decide the amount of precision needed, and


       then derive sample size estimates.


                 Now, indeed, when those sample size


       estimates begin to be large, we have to face the


       challenge of how do we do those studies.  Do they


       require multicenter studies?  Do they require


       longer periods and more effort to recruit?  Do they


       require larger budgets?


                 These are real factors.  In the real


       world, of course, we must live with the available


       data and the available resources as we collect


       information.  I do think there is an important


       distinction between the sample needed to estimate


       with fairly reasonable or conventional confidence a


       rate of 10 percent and the sample needed to make


       estimates of thresholds.


                 Depending on how precise your estimates


       could be, your samples might be about that size or


       they might be much larger.  There should be more


       conscious decision making in setting the size of


       those samples as well as thinking about the


       thresholds themselves.


                 CHAIRMAN DURST:  David and then Erica.


                 MR. ORYANG:  Yes, David Oryang.  Further


       about some of the methodologies, a lot of times if


       the resources are available, time being one


       resource, and the need is there to really go do a


       more in-depth analysis, then the risk-assessment-


       based approach, looking at dose response and


       exposures, would be the method to go, but the data


       is not currently available.


                 I will just suggest that sometimes if one


       does take the risk-assessment-based approach, you


       can still do it, but there would be a lot of


       uncertainty in a lot of the parameters.


                 To the extent that they can be


       transparently presented, maybe it is still viable.


       I haven't really seen the evidence that we have


       enough on some of the dose responses and exposures.


                 I know that in this report there is enough


       stated in there, and it is suggested that the


       risk-assessment-based approach be the preferred


       approach for the allergens but not for the glutens.


                 Maybe that is also because of the acute


       nature of the allergens.  I mean, the consequence


       of not looking further into it seems to be more


       acute than in the gluten case.


                 I concur with FDA in some of these


       recommendations.  I would just say that if the


       resources are available and more information is


       available, the risk-assessment-based approach is


       the better approach.


                 CHAIRMAN DURST:  Erica.


                 DR. BRITTAIN:  Yes, I really want to echo


       what Marc said.  This magical sample size of 29


       that we kept hearing I really think is not quite,


       even if you want to just exclude a 10 percent rate,


       which doesn't seem like really enough for the


       threshold setting, it is not set up the way I think


       people would normally want to set things up to have


       appropriate statistical power.  That is one


       relatively minor point.


                 It all goes back to what I said originally


       that I think you need to set a precise goal of how


       much risk is acceptable, and that will drive the


       sample size.  If that sample size is way beyond


       what can be done, then I think you have to go to


       the modeling approach with the right data.


                 CHAIRMAN DURST:  Further discussion?




                 DR. KELLY:  Ciaran Kelly.  I just wanted


       to reinforce the comment that has already been made


       of the value of including population experiences


       within the safety assessment.


                 Unfortunately, not only is there a wealth


       of experience, but there are also a number of


       publications that document the efficacy in a


       population of certain levels of gluten exposure.


                 I think that if one were to consider the


       more conservative thresholds that are currently in


       use, there would be the likelihood that those


       thresholds would be dangerous as opposed to safe


       would seem to be very low.


                 CHAIRMAN DURST:  Mark.


                 DR. NELSON:  Yes, Mark Nelson.  I wanted


       to come back to comments that Marc and Erica made,


       but maybe emphasize it a little differently.  I


       fully agree with basing this all on science and


       having statistical rigor, but we also have to make


       sure we are not having to prove we're the enemy or


       the good.


       We may need to adjust the studies for different


       allergens, for example, depending on the severity


       of the response, and so on.


                 We shouldn't forget that the sample size


       used to support the hypoallergenic infant formula


       was also for a population whose sole source of


       nutrition was the infant formula that they were


       taking in.  I mean, safety was clearly considered


       in that situation, and, again, it serves the


       greater portion of that population.


                 CHAIRMAN DURST:  Any further discussion?


                 (No response.)


                 CHAIRMAN DURST:  We are ready to move on


       to the second question.  I will read it again:


                 "Are FDA's criteria for selecting and


       evaluating the available data appropriate?  If not,


       should any of the criteria be modified or deleted?


       Please describe any changes you would like to see


       and why.  Are there additional criteria FDA should




                 Who would like to start that off?


                 DR. BRITTAIN:  I think we have already


       covered all of this.  I don't know if there is


       anything else?


                 CHAIRMAN DURST:  Yes, I don't know if


       there are any more.




                 DR. SILVERSTEIN:  Mark Silverstein.  There


       was a very useful document prepared and funded by


       the Agency for Healthcare Research and Quality.  I


       mentioned it yesterday, and it was "Methods for


       Evaluating the Strength of Evidence."  It was I


       think prepared by one of the evidence-based


       practice centers under contract from the Agency for


       Healthcare Research and Quality.  It has been


       published, and it is available on their Web site.


       It basically summarizes a set of methodologic


       criteria that you would use in doing, evaluating,


       grain- or mice-controlled trials, cohort studies,


       studies or diagnostic tests.


                 In looking through the list of the


       criteria that are in the FDA report, almost all of


       the criteria are mentioned, maybe not in exactly


       the same format as in that publication.  It seems


       to me, that since it is our taxpayer dollars at


       work and other agencies have already developed


       this, it would be useful to look at it.


                 I do believe the diagnostic test section,


       which would be relevant for some of the food


       challenges, has a different way of phrasing some of


       the focus on the selection of the patients.


                 I do think it would be a useful resource


       both to cite and perhaps to look at to see that the


       categories suggested by that thoughtful review are


       well covered in all of the categories.


                 CHAIRMAN DURST:  Okay.  Ciaran and then




                 DR. KELLY:  Ciaran Kelly.  Yes, I have


       just one comment, and it has to do with the


       criteria for evaluating analytic methods.  To my


       mind, transparency of the method, an adequate


       description of the specific methodology, would be


       important so that potential biases or weaknesses


       that are inherent within the methodology could be


       examined in addition to the other criteria that you




                 CHAIRMAN DURST:  Erica.


                 DR. BRITTAIN:  I just have a very brief


       comment.  In terms of beefing up the summary of


       studies in the appendix, maybe along the lines that


       Marc suggested, one thing that is not in there is


       number of patients in each study.  That seems like


       a critical omission.


                 CHAIRMAN DURST:  Anything else?




                 MS. HALLORAN:  Jean Halloran.  I was


       intrigued by the suggestion from Dr. Taylor who


       mentioned that clinicians have data on NOAELs and


       LOAELs for their patients in their records.  This


       is certainly not data which is a


       placebo-controlled, double-blind study; it is not


       peer reviewed; and it is not many other things.


                 Given that there seems to be such a dirth


       of data, especially for certain allergens, I am


       wondering whether any effort could be made or


       whether there would be any value to FDA asking for


       such data just to somehow get a vague idea of what


       is going on in those areas, whether it is possible


       to do that, or whether once data is submitted, it


       gets a life of its own and it is more trouble than


       it's worth?


                 CHAIRMAN DURST:  Okay.  That actually


       leads us into the third question.


                 DR. BRITTAIN:  Well, I mean, it relates to


       this, which is that my concern about that is that


       if those studies were done almost exclusively on


       patients for whom they were trying to confirm a


       diagnosis, they would be really biased.


                 Even if there is a large number of them,


       if the information came from it is really biased


       and is wrong, then it doesn't really help that you


       have a lot of data.


                 CHAIRMAN DURST:  Soheila.


                 DR. MALEKI:  Soheila Maleki.  Just one


       comment.  The studies that they used for a


       challenge, and I think Suzanne can confirm that, is


       the doses that are used are often much higher than


       threshold doses.  Actually, if you use that data,


       you would be targeting people that have really high


       threshold doses, if they didn't react at that




                 CHAIRMAN DURST:  Margaret.


                 DR. McBRIDE:  I think, though, that those


       concerns about that kind of data could be handled


       by only including subjects who responded.


       Obviously, you don't want subjects that didn't


       respond, because you don't even know if they are


       sensitive.  There are ways still of looking at that


       data and possibly having something.


                 CHAIRMAN DURST:  Suzanne.


                 DR. TEUBER:  Suzanne Teuber.  That data,


       it actually would be very useful to have if we are


       trying to start characterizing subpopulations of


       patients.  Because we know that the vast majority


       of patients where there is likely this NOAEL data


       that just wasn't published are patients who are


       children with atopic dermatitis.


                 That is a distinct subgroup with usually


       not as severe a reaction, and so it might be very


       useful to have that, because we still need more


       data.  We can help characterize more, then.


                 CHAIRMAN DURST:  Since we are dealing with


       question three, let me just read it into the






                 CHAIRMAN DURST:  "Recognizing that some of


       the key studies (i.e., challenge studies) are


       ongoing, what if any use of preliminary data that


       have not been peer reviewed for establishing


       thresholds is appropriate?"


                 Now we can continue.


                 David, did you have your hand up?


                 MR. ORYANG:  Yes, I did have my hand up.


       Just briefly, about the data.  I don't see very


       much put in there about expert opinion and clear


       methods of being able to elicit some of this kind


       of information that is kept in records, and so


       forth, from a panel of experts and clearly


       documented in a way that can be presented


       scientifically in the document to be included as


       part of the record in how the decision came to be.


                 I think it would be useful if there was a


       formal process for getting that kind of information


       from doctors and other people who can be considered


       experts on those specific areas, elicit that


       information formally and document it, and then show


       a clear method of how you came from the broad


       opinion to the narrowed result or determination


       that was made.


                 I think that is also a good process of


       getting that kind of unpublished or informal


       information which can be looked at as a knowledge,


       which is important in decision making.


                 CHAIRMAN DURST:  Soheila.


                 DR. MALEKI:  Soheila Maleki.  Again, I


       mean, of course any data that any scientist is


       beautiful and wonderful to get.  But, again, I


       don't think that in establishing thresholds, which


       is what we are looking at, that the challenge


       studies would be.


                 Again, it is wonderful, yes, if we were


       going to divide people into subpopulations.  Bottom


       line, we are looking at the most severe reactions,


       which I don't think will be included in that data


       because of the high doses of the challenge, or


       often higher doses.


                 DR. BRITTAIN:  And the populations that


       would undergo those challenges.


                 DR. MALEKI:  Yes.  Essentially for this,


       yes.  I mean, of course it is wonderful to have the


       data.  What scientist or doctor or agency doesn't


       want more data?  But bottom line that is --


                 CHAIRMAN DURST:  Suzanne.


                 DR. TEUBER:  Suzanne Teuber.  Just to


       address Mr. Oryang's comments, actually the First


       Threshold Conference that was held, the paper by


       Steve Taylor and all, that was bringing together


       people who had unpublished data about thresholds,


       and from there it has gone on to the current


       consensus protocol.


                 The data that was referred to by Dr.


       Taylor was something that was brought to the table,


       but again it was this population that was more


       atopic dermatitis.  I still think it would be


       interesting to have it.  It would cost money to get


       it, to pay somebody.


                 However, it is true it would not give


       information directly related to the


       safety-assessment threshold information we want.


       It is just population data that is of interest.


                 CHAIRMAN DURST:  Mark.


                 DR. NELSON:  Mark Nelson.  I guess I would


       echo Jean's comment and a lot of other people, to


       try to get more data.  What I understood Steve


       Taylor to describe, the specific example he gave,


       was Hugh Sampson's work.


                 This is the extra data from a


       peer-reviewed study, which strikes me, hearing the


       clinicians speak and others, that this would be


       very useful for helping specify the uncertainty


       factors we have talked about and also help us maybe


       with some of these subjective responses.  I don't


       know, I haven't seen the data.


                 CHAIRMAN DURST:  Jeff.


                 DR. BARACH:  Jeff Barach.  As we heard,


       other countries are struggling with the issues of


       allergens also.  I would just make note that the


       European Food Safety Authority and the European


       Commission have put together a Directive




                 I would encourage the FDA to contact the


       European Food Safety Authority to find out if they


       have any data that would be of interest to our


       group as they work on the issue.


                 CHAIRMAN DURST:  Soheila.


                 DR. MALEKI:  Soheila Maleki.  I think that


       is a really good point, and I also think Health


       Canada, but I think they have already talked to


       them about it.  That is a very good point.


                 CHAIRMAN DURST:  Margaret.


                 DR. McBRIDE:  I understand the concern


       about the difference, the potential difference, in


       dosing for challenge tests versus threshold


       testing.  We have already established that if there


       is a LOAEL in the absence of a NOAEL, that is not


       very useful.


                 On the other hand, if within that data


       there are individuals that prove to be sensitive to


       whatever is being test and the NOAEL is available


       as well as the LOAEL, that is clearly relevant




                 CHAIRMAN DURST:  Petr.


                 DR. BOCEK:  Petr Bocek.  Just a quick


       comment to that.  Yes, it is very valuable, but it


       has to be done with the right population.  If that


       was a patient where it was a diagnostic challenge,


       a question of biology, it is not as valuable as


       somebody who has a clear-cut clinical presentation


       of anaphylaxis to a food allergen.  Yes, that is


       the right person to look for a threshold.


                 CHAIRMAN DURST:  Any further discussion?




                 DR. KELLY:  Ciaran Kelly.  I just wanted


       to perhaps more directly address the question about


       non-peer-reviewed experimentation.  Clearly, the


       presentation that Dr. Fasano gave to us yesterday


       is not peer reviewed and published, but,


       nonetheless, it is directly pertinent and relevant


       to the question at hand and also is performed by a


       well-recognized, expert group of investigators.


                 Clearly, that is a double-blind,


       randomized-controlled trial.  Clearly, those data


       are highly relevant.  Although it is likely that


       they will be published within the next year, that


       publication process is sometimes very hard to


       predict, and it could be much longer than a year.


       I would feel personally, and I don't know if the


       rest of the Committee agrees, that those data are


       highly relevant.


                 CHAIRMAN DURST:  Any further discussion?


                 (No response.)


                 CHAIRMAN DURST:  Before we wrap things up,


       I would also like to ask does anyone have any


       specific comments on anything in the report,


       anything that jumped out at them that needs some


       modification or correction?


                 Yes, Ciaran.

                 DR. KELLY:  Ciaran Kelly.  I do have some


       minor suggestions, but I don't want to take up the


       Committee's time with it.  What is the mechanism?


       Should I submit some --


                 MRS. MOORE:  He has asked the question, so


       go ahead.  Go ahead.


                 CHAIRMAN DURST:  I mean, is it proper just


       to provide that to the Working Group?


                 DR. KELLY:  I don't want to waste the


       Committee's time with very, very minor things.


                 MRS. MOORE:  Okay.  You can send it to me.


                 DR. KELLY:  I can provide that in the form


       of a memo.


                 MRS. MOORE:  Okay.


                 CHAIRMAN DURST:  Again, I want to refer


       back to Steve.  Any specific questions that you


       might have before we wind things up here?


                 DR. GENDEL:  (Off microphone.)  Yes, I


       just want to remind everyone that there is a


       mechanism for submitting information through the


       docket.  You can access that through the FDA


       homepage.  Any information that is relevant can be

       put in there.


                 MRS. MOORE:  Steve, start from the top


       because you weren't heard from the beginning of


       your statement.


                 DR. GENDEL:  Okay.  This is Steve Gendel.


       The response was that any information can be


       submitted through the docket, which is available.


       Any relevant information can be submitted through


       the docket available through the FDA homepage.


                 CHAIRMAN DURST:  Okay.  I think we are at


       the point now that I can ask Mr. Landa to make some


       closing comments.


                             Closing Comments


                 MR. LANDA:  Thank you, Dr. Durst.  I will


       be very brief.  First, I just want to reiterate Dr.


       Brackett's thanks to all of the members of the


       Committee for lending us your expertise for these


       several days.  We rely heavily on experts from


       outside as well as within the Agency.  Of course,


       this is one of the principle ways in which we


       obtain outside expertise.


                 The second point, just in case not


       everyone heard it, the point Steve Gendel made.


       The docket will remain open for another several


       weeks until the middle of August.  Anyone who has


       comments on the report please get them to us


       through the docket.


                 We will consider any comments from the


       public as well as the results and the comments,


       sort of consensus statements, from this meeting in


       making any changes to the draft report and in


       taking our next steps after the draft report is




                 The last thing is I would just like to


       reiterate the thanks noted earlier to Marcia Moore


       and her colleagues for putting on the meeting.


       Thank you.


                 MRS. MOORE:  Thank you.


                 CHAIRMAN DURST:  Thank you.


                 I believe Marcia said the transcript of


       this meeting would be available at the end of




                 MRS. MOORE:  Yes.


                 CHAIRMAN DURST:  Without any further


       comments, I will declare this meeting adjourned.


                 Thank you very much everyone.


                 (Whereupon, at 9:37 a.m., the meeting was